Fungal infections have become an emerging public health threat, heightened due to the increasing size of an immunocompromised patient population (Arendrup, M. C. (2010) Epidemiology of invasive candidiasis. Curr. Opin. Crit. Care 16, 445-452). This population includes patients with AIDS, primary immune deficiency, and those who are immunocompromised due to chemotherapy or organ and bone marrow transplantation.
Globally, Candida species are the predominant cause of invasive systemic fungal infections, with a reported prevalence at 6.9 cases per 1000 patients (Kett, D. H. et al. (2011) Extended prevalence of infection in ICU study (EPIC II) group of investigators Candida bloodstream infections in intensive care units: analysis of the extended prevalence of infection in intensive care unit study. Crit. Care Med. 39, 665-670). In the United States, Candida infections rank fourth among all hospital-acquired systemic infections in intensive care units (Wisplinghoff, H. et al. (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin. Infect. Dis. 39, 309-317). In most population-based studies, Candida infections represent the seventh to tenth most common bloodstream infections (Kullberg, B. J. and Arendrup, M. C. (2015) Invasive candidiasis. N. Engl. J. Med. 373, 1445-1456). Additionally, many patients are now infected with other fungal species, including Aspergillus fumigatus, Aspergillus nidulans, and Cryptococcus neoformans (Mayr, A. and Lass-Florl, C. (2011) Epidemiology and antifungal resistance in invasive aspergillosis according to primary disease: review of the literature. Eur. J. Med. Res. 16, 153-157; van der Linden, J. W. et al., (2015) Prospective multicenter international surveillance of azole resistance in Aspergillus fumigatus. Emerg. Infect. Dis. 21, 1041-1044; Sloan, D. J. and Parris, V. (2014) Cryptococcal meningitis: epidemiology and therapeutic options. Clin. Epidemiol. 6, 169-182).
Common therapeutic agents used to treat fungal infections include azoles (e.g., fluconazole (FLC), itraconazole (ITC), posaconazole (POS), and voriconazole (VOR)), polyenes (e.g., amphotericin B (AmB), nystatin (NYS), and candicidin (CAN)), allylamines (e.g., butenafine, naftifine, and terbinafine), and echinocandins (e.g., micafungin, caspofungin, and anidulafungin). These drugs function by different mechanisms of action: (i) inhibition of the cytochrome P450 enzyme 14α-demethylase (azoles); (ii) introduction of transmembrane channel leading to monovalent ion leakage (polyenes); (iii) inhibition of squalene epoxidase (allylamines); and (iv) inhibition of synthesis of glucan in the fungal cell wall via the enzyme 1,3-β-glucan synthase (echinochandins) (Pasko, M. T. et al. (1990) Fluconazole: a new triazole antifungal agent. DICP 1990, 24, 860-867; Zumbuehl, A.et al. (2004) An amphotericin B-fluorescein conjugate as a powerful probe for biochemical studies of the membrane. Angew. Chem. 43, 5181-5185; Baginski, M. and Czub, J. (2009) Amphotericin B and its new derivatives-mode of action. Curr. Drug Metab. 10,459-469; Morris, M. I. and Villmann, M. (2006) Echinocandins in the management of invasive fungal infections, part 1. Am. J. Health Syst. Pharm. 63, 1693-1703).
Due to improper usage of these antifungal agents, such as insufficient dosages and durations of treatment, more drug-resistant fungal strains have evolved (Sanguinetti, M. et al. (2015) Antifungal drug resistance among Candida species: mechanisms and clinical impact. Mycoses 58 Suppl 2, 2-13.; Kanafani, Z. A. and Perfect, J. R. (2008) Antimicrobial resistance: resistance to antifungal agents: mechanisms and clinical impact. Clin. Infect. Dis. 46, 120-128; Shah, D. N. et al. (2012) Impact of prior inappropriate fluconazole dosing isolation of fluconazole-nonsusceptible Candida species in hospitalized patients with candidemia. Antimicrob. Agents Chemother. 56, 3239-3243). Additionally, new evidence suggests that antibacterials also contribute to the development of fungal resistance. (Ben-Ami, R.et al. (2012) Antibiotic exposure as a risk factor for fluconazole-resistant Candida bloodstream infection. Antimicrob. Agents Chemother. 56, 2518-2523).
Currently, three strategies have been employed to overcome antifungal drug resistance. The first strategy is the development of compounds with novel mechanisms of action distinct from previous antifungal agents. For instance, compound E1210 was discovered as a novel first-in-class antifungal compound by the Tsukuba Research Laboratories of Eisai Co., Ltd. This compound was discovered to inhibit fungal glycosylphosphatidylinositol (GPI) biosynthesis and validated in murine models of candidiasis, aspergillosis, and fusariosis (Hata, K. et al. (2011) Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis. Antimicrob. Agents Chemother. 55, 4543-4551).
The second strategy is the combination of two antifungal agents. In the literature, there are many examples using two compounds in conjunction to produce synergistic antifungal activity and reduce resistance as well as toxicity (Kontoyiannis, D. P. and Lewis, R. E. (2004) Toward more effective antifungal therapy: the prospects of combination therapy. Br. J. Haematol. 126, 165-175; Day, J. N. et al. (2013) Combination antifungal therapy for cryptococcal meningitis. N. Engl. J. Med. 368, 1291-1302). Specifically, in patients diagnosed with cryptococcal meningitis, the combination therapy of flucytosine and AmB was shown to be essential for successful clinical outcomes (Perfect, J. R. et al. (2010) Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 50, 291-322). Recently, it was also found that a combination of azoles and analogues of the aminoglycoside antibiotics tobramycin and kanamycin B resulted in favorable synergistic effects against drug-resistant Candida albicans strains (Shrestha, S. K., et al. (2015) A combination approach to treating fungal infections. Sci. Rep. 5, 17070; Fosso, M. Y. et al. (2015) Synthesis and bioactivities of kanamycin B-derived cationic amphiphiles. J. Med. Chem. 58, 9124- 9132).
The third strategy is the use of known compounds for new applications. For example, the decongestant drug octodrine was identified as a broad-spectrum antifungal compound. Kim, K. et al. (2015) Repurposing FDA approved drugs against the human fungal pathogen, Candida albicans. Ann. Clin. Microbiol. Antimicrob. 14, 32.